This proposal describes a 5 year program designed to support the development of the PI into an independent investigator in viral immunology and vaccine design. During this program the PI will build upon a strong foundation in human immunology as a means to transition into a career in translational virology and vaccinology. In order to attain this goal, this proposal involves the complete progression from discovery and description of important antigenic regions of the Venezuelan Equine Encephalitis (VEE) virus through the design, construction, and preclinical testing of a new vaccine for prevention of VEE infection. In order to address the lack of any commercially available treatment or vaccine for VEE, the research Aims of this proposal are: 1) To characterize the fine specificity of the Venezuelan Equine Encephalitis virus humoral immune response to two key antigenic targets: VEE structural proteins E1 and E2, 2) To identify which common antigenic targets of E1 and E2 elicit protective immunity and establish the relative contribution of individual antibody specificities, 3) To characterize the cellular immune responses to VEE in individuals exposed to the live, attenuated TC-83 strain of virus through vaccination, and 4) Test the ability of the B and T cell targets identified in Aims 1-3 as candidate vaccine antigens in a small animal model. In addition to practical training in new methodologies and techniques, the candidate will participate in an integrated curriculum designed to foster the development of scientific independence. This curriculum will involve seminars and symposia on virology and vaccines, presentation of research at national meetings, didactic training through classical coursework as well as national workshops, and close personal interactions with a carefully selected Advisory Committee of experts on the basic and clinical research aspects of virology and vaccine design and implementation. This proposal is designed to take full advantage of the myriad strengths of two closely allied and situated Universities - Duke and UNC-Chapel Hill - in order to maximize the exposure and training aspects of the program. This environment fosters a collaborative spirit and provides an ideal setting for launching an independent science career. RELEVANCE (See instructions): Venezuelan Equine Encephalitis is a major human pathogen throughout parts of North and South America which can cause severe headaches, myalgias, prostration, encephalitis, and even death. It is a CDC- designated Category B Select Agent, identifying its potential use as an agent of bioterrorism, and in fact VEE is one of the few agents that has actually been weaponized by both the US and USSR in the past. There are currently no known therapeutic agents or commercially available vaccines for the prevention of VEE infection.